In initial studies we established with Western blot studies that the LRRK2 polymorphism was associated with increased expression of LRRK2 and was thus a gain of function mutation. This finding correlated with the effect of LRRK2 over-expression since mice with this abnormality exhibited more severe DSS-colitis. In addition, dendritic cells from LRRK2 transgenic mice exhibited increased Dectin-1-mediated induction of TNF-alpha and IL-23 associated with phosphorylation of MAPK, NF-kappaB and NFAT signaling components, positive NF-kappaB and NFAT reporter assays and nuclear translocation of NFAT. In further studies we established that Dectin-1 stimulation of dendritic cells results in K-63 polyubiquitination of LRRK2 and that this is mediated by TAB2 and TRAF6. In addition, LRRK2 in association with TRAF6 induces K-63 polyubiquitination of NEMO and in a reporter assay both LRRK2 and TAB2 or LRRK2 and TRAF6 induces NK-kappaB in a reporter assay. Thus, LRRK2 emerges as a major facilitator of NF-kappaB activation. In studies of the relation of LRRK2 to autophagy we showed with LRRK2KOxLC3gfp transgenic mice and LRRK2Tgxgfp transgenic mice that LRRK2 deletion and over-expression was associated with increased autophagy and decreased autophagy respectively. This result was confirmed by studies of Western blot studies of LC3 conversion. As to the mechanism of these effects on autophagy, we showed that LRRK2 binds to beclin-1 in Western blot and duolink studies, LRRK2 enhances the interaction of beclin-1 with Rubicon and LRRK2 in association with TAB2 and Rubicon induces beclin-1 degradation. Thus, LRRK2 binds to the phagosomal membrane and inhibits autophagy via it ability to enhance degradation of beclin-1. In preliminary studies we have evidence that inhibition of autophagy leads to enhanced LRRK2 expression; thus, it appears likely that increased LRRK2 expression in patients with LRRK2 polymorphisms exhibit enhanced pro-inflammatory responses to innate stimuli because such increased expression causes inhibition of autophagy and feedback LRRK2-mediated stimulation of NF-kappaB activation or NFAT activation. In a final round of studies we established that LRRK2 inhibitors reverse the effects of LRRK2 on autophagy and NF-kappaB activation and ameliorate DSS-colitis. Thus, such inhibitors emerge as a possible treatment of patients with Crohn's disease, particularly those with LRRK2 polymorphisms.